African Malaria Mosquito Acetylcholinesterase

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==Model: Bound Acetylcholinesterase (African Malaria Mosquito) Inhibitor Complex - by Yuan-Ping Pang==
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==Model: Acetylcholinesterase of the African Malaria Mosquito - by Yuan-Ping Pang==
<applet load='Ap-agache.pdb' size='300' color="white" frame='true' spin="on" align='right' script="African_Malaria_Mosquito_Acetylcholinesterase/Ap-agache_rainbow/2" / caption='AChE - African Malaria Mosquito' />
<applet load='Ap-agache.pdb' size='300' color="white" frame='true' spin="on" align='right' script="African_Malaria_Mosquito_Acetylcholinesterase/Ap-agache_rainbow/2" / caption='AChE - African Malaria Mosquito' />
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Unlike mammals, many disease-transmitting or crop-pest insects have two AChE genes (AP and AO) [1-6]. Interestingly, a free cysteine (Cys) residue, for example, Cys286 of AP-AChE in Anopheles gambiae sensu stricto (AP-AgAChE), is present at the entrance to the active site of insect AP-AChEs but not at that of AO-AChEs and AChEs from mammals, birds, and fish [7-9]. Mosquitoes have an additional arginine residue (Arg339 of AP-AgAChE) at the rim of the AP-AChE active site that appears to be genus-specific [8]. Methanethiosulfonate-containing molecules designed to target the active-site Cys residue reportedly inhibited irreversibly most AChE activity extracted from aphids, the African malaria mosquito, the yellow fever mosquito and the northern house mosquito, while an identical exposure caused no effect on the human AChE [10,11]. Most recent studies showed that the same Cys-targeting molecules irreversibly inhibited most AChE activity extracted from cockroaches, flour beetles, the bed bug and a wasp [manuscript under review]. The irreversible inhibition is primarily caused by the formation of a disulfide bond between the inhibitor and the Cys residue as evident from the reversal of inhibition by 2-mercaptoethanol [10,11]. These results suggest that AP-AChE is a viable target for developing insect-selective pesticides to control crop damage and disease vectors and to alleviate resistance problems of current insecticides with reduced toxicity toward non-target species. The coordinates of AP-AgAChE in its bound state [12] is refined from a published computer model (PDB code: 2AZG) [8,13] using a modified AMBER force field [to be published] and might be useful for structure-based design of anti-malaria agents [14].
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Unlike mammals, many disease-transmitting or crop-pest insects have two AChE genes (AP and AO) <ref>J.-R. Gao, K.Y. Zhu, Increased expression of an acetylcholinesterase gene may confer organophosphate resistance in the greenbug, Schizaphis graminum (Homoptera: Aphididae), Pesticide Biochemistry and Physiology 73(3) (2002) 164-173.</ref><ref>Gao JR, Kambhampati S, Zhu KY (2002) Molecular cloning and characterization of a greenbug (Schizaphis graminum) cDNA encoding acetylcholinesterase possibly evolved from a duplicate gene lineage. Insect Biochem Mol Biol 32: 765-775.</ref><ref>Weill M, Fort P, Berthomieu A, Dubois MP, Pasteur N, et al. (2002) A novel acetylcholinesterase gene in mosquitoes codes for the insecticide target and is non-homologous to the ace gene in Drosophila. Proc Biol Sci 269: 2007-2016.</ref><ref>Baek JH, Kim JI, Lee D-W, Chung BK, Miyata T, et al. (2005) Identification and characterization of ace1-type acetylcholinesterase likely associated with organophosphate resistance in Plutella xylostella. Pestic Biochem Physiol 81: 164-175.</ref><ref>Kono Y, Tomita T (2006) Amino acid substitutions conferring insecticide insensitivity in Ace-paralogous acetylcholinesterase. Pestic Biochem Physiol 85: 123-132.</ref><ref>Mamiya A, Ishikawa Y, Kono Y (1997) Acetylcholinesterase in insecticide resistant Culex tritaeniorhynchus: characteristics accompanying insensitivity to inhibitors. Appl Entomol Zool 32: 37-44.</ref>. Interestingly, a free cysteine (Cys) residue, for example, Cys286 of AP-AChE in ''Anopheles gambiae'' sensu stricto (AP-AgAChE), is present at the entrance to the active site of insect AP-AChEs but not at that of AO-AChEs and AChEs from mammals, birds, and fish
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<ref>Pezzementi L, Rowland M, Wolfe M, Tsigelny I (2006) Inactivation of an invertebrate acetylcholinesterase by sulfhydryl reagents: the roles of two cysteines in the catalytic gorge of the enzyme. Invert Neurosci 6: 47-55.</ref><ref name="pang_2006_PLoS"> Y.-P. Pang, Novel Acetylcholinesterase Target Site for Malaria Mosquito Control, PLoS ONE 1 (2006) e58. [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0000058 Paper]</ref><ref>PMID: 17046256 </ref>. Mosquitoes have an additional arginine residue (Arg339 of AP-AgAChE) at the rim of the AP-AChE active site that appears to be genus-specific<ref name="pang_2006_PLoS"/>. Methanethiosulfonate-containing molecules designed to target the active-site Cys residue reportedly inhibited irreversibly most AChE activity extracted from aphids, the African malaria mosquito, the yellow fever mosquito and the northern house mosquito, while an identical exposure caused no effect on the human AChE
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<ref name="pang_2009a_PLoS">Y.-P. Pang, S.K. Singh, Y. Gao, T.L. Lassiter, R.K. Mishra, K.Y. Zhu, S. Brimijoin, Selective and Irreversible Inhibitors of Aphid Acetylcholinesterases: Steps Toward Human-Safe Insecticides, PLoS ONE 4 (2009) e4349. [http://www.plosone.org/article/info%3Adoi/10.1371/journal.pone.0004349 Paper]</ref>
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<ref name="pang_2009b_PLoS">Pang Y-P, Ekstrom F, Polsinelli GA, Gao Y, Rana S, et al. (2009) Selective and irreversible inhibitors of mosquito acetylcholinesterases for controlling malaria and other mosquito-borne diseases. [http://www.plosone.org/article/info%3Adoi/10.1371/journal.pone.0006851 Paper]</ref>. The irreversible inhibition is primarily caused by the formation of a disulfide bond between the inhibitor and the Cys residue as evident from the reversal of inhibition by 2-mercaptoethanol <ref name="pang_2009a_PLoS"/><ref name="pang_2009b_PLoS"/>. These results suggest that AP-AChE is a viable target for developing insect-selective pesticides to control crop damage and disease vectors and to alleviate resistance problems of current insecticides with reduced toxicity toward non-target species. The model of AP-AgAChE in its bound state <ref>The model of AP-AgAChE in its bound state was released at [http://mayoresearch.mayo.edu/mayo/research/camdl/protein-structure-prediction.cfm Mayo Research Protein Structure Prediction] on Dec 12, 2009</ref> is refined from a published computer model (PDB code: 2AZG)<ref name="pang_2006_PLoS"/><ref>Per the Protein Data Bank record, 2AZG was deposited to Protein Data Bank on Sept 5, 2005, eight months prior to the online publication of reference 7.</ref> using a modified AMBER force field [to be published] and might be useful for structure-based design of anti-malaria agents <ref>This author thanks Professor Joel L. Sussman and his colleagues for their creation and maintenance of PROTEOPEDIA that permits archiving computational models of macromolecular structures and assessment of protein structure prediction made prior to experimental structures. </ref>.
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==References & Notes==
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'African_Malaria_Mosquito_Acetylcholinesterase/Ap-agache_cartoon/1'>
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<references/>

Revision as of 07:07, 19 December 2009

Theoretical Model: The protein structure described on this page was determined theoretically, and hence should be interpreted with caution.

Model: Acetylcholinesterase of the African Malaria Mosquito - by Yuan-Ping Pang

AChE - African Malaria Mosquito

Drag the structure with the mouse to rotate

Unlike mammals, many disease-transmitting or crop-pest insects have two AChE genes (AP and AO) [1][2][3][4][5][6]. Interestingly, a free cysteine (Cys) residue, for example, Cys286 of AP-AChE in Anopheles gambiae sensu stricto (AP-AgAChE), is present at the entrance to the active site of insect AP-AChEs but not at that of AO-AChEs and AChEs from mammals, birds, and fish [7][8][9]. Mosquitoes have an additional arginine residue (Arg339 of AP-AgAChE) at the rim of the AP-AChE active site that appears to be genus-specific[8]. Methanethiosulfonate-containing molecules designed to target the active-site Cys residue reportedly inhibited irreversibly most AChE activity extracted from aphids, the African malaria mosquito, the yellow fever mosquito and the northern house mosquito, while an identical exposure caused no effect on the human AChE [10] [11]. The irreversible inhibition is primarily caused by the formation of a disulfide bond between the inhibitor and the Cys residue as evident from the reversal of inhibition by 2-mercaptoethanol [10][11]. These results suggest that AP-AChE is a viable target for developing insect-selective pesticides to control crop damage and disease vectors and to alleviate resistance problems of current insecticides with reduced toxicity toward non-target species. The model of AP-AgAChE in its bound state [12] is refined from a published computer model (PDB code: 2AZG)[8][13] using a modified AMBER force field [to be published] and might be useful for structure-based design of anti-malaria agents [14].

References & Notes

  1. ↑ J.-R. Gao, K.Y. Zhu, Increased expression of an acetylcholinesterase gene may confer organophosphate resistance in the greenbug, Schizaphis graminum (Homoptera: Aphididae), Pesticide Biochemistry and Physiology 73(3) (2002) 164-173.
  2. ↑ Gao JR, Kambhampati S, Zhu KY (2002) Molecular cloning and characterization of a greenbug (Schizaphis graminum) cDNA encoding acetylcholinesterase possibly evolved from a duplicate gene lineage. Insect Biochem Mol Biol 32: 765-775.
  3. ↑ Weill M, Fort P, Berthomieu A, Dubois MP, Pasteur N, et al. (2002) A novel acetylcholinesterase gene in mosquitoes codes for the insecticide target and is non-homologous to the ace gene in Drosophila. Proc Biol Sci 269: 2007-2016.
  4. ↑ Baek JH, Kim JI, Lee D-W, Chung BK, Miyata T, et al. (2005) Identification and characterization of ace1-type acetylcholinesterase likely associated with organophosphate resistance in Plutella xylostella. Pestic Biochem Physiol 81: 164-175.
  5. ↑ Kono Y, Tomita T (2006) Amino acid substitutions conferring insecticide insensitivity in Ace-paralogous acetylcholinesterase. Pestic Biochem Physiol 85: 123-132.
  6. ↑ Mamiya A, Ishikawa Y, Kono Y (1997) Acetylcholinesterase in insecticide resistant Culex tritaeniorhynchus: characteristics accompanying insensitivity to inhibitors. Appl Entomol Zool 32: 37-44.
  7. ↑ Pezzementi L, Rowland M, Wolfe M, Tsigelny I (2006) Inactivation of an invertebrate acetylcholinesterase by sulfhydryl reagents: the roles of two cysteines in the catalytic gorge of the enzyme. Invert Neurosci 6: 47-55.
  8. ↑ 8.0 8.1 8.2 Y.-P. Pang, Novel Acetylcholinesterase Target Site for Malaria Mosquito Control, PLoS ONE 1 (2006) e58. Paper
  9. ↑ Pang YP. Species marker for developing novel and safe pesticides. Bioorg Med Chem Lett. 2007 Jan 1;17(1):197-9. Epub 2006 Oct 12. PMID:17046256 doi:10.1016/j.bmcl.2006.09.073
  10. ↑ 10.0 10.1 Y.-P. Pang, S.K. Singh, Y. Gao, T.L. Lassiter, R.K. Mishra, K.Y. Zhu, S. Brimijoin, Selective and Irreversible Inhibitors of Aphid Acetylcholinesterases: Steps Toward Human-Safe Insecticides, PLoS ONE 4 (2009) e4349. Paper
  11. ↑ 11.0 11.1 Pang Y-P, Ekstrom F, Polsinelli GA, Gao Y, Rana S, et al. (2009) Selective and irreversible inhibitors of mosquito acetylcholinesterases for controlling malaria and other mosquito-borne diseases. Paper
  12. ↑ The model of AP-AgAChE in its bound state was released at Mayo Research Protein Structure Prediction on Dec 12, 2009
  13. ↑ Per the Protein Data Bank record, 2AZG was deposited to Protein Data Bank on Sept 5, 2005, eight months prior to the online publication of reference 7.
  14. ↑ This author thanks Professor Joel L. Sussman and his colleagues for their creation and maintenance of PROTEOPEDIA that permits archiving computational models of macromolecular structures and assessment of protein structure prediction made prior to experimental structures.

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